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Glutamate for Metabolic Intervention in Coronary Surgery (GLUTAMICS)

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ClinicalTrials.gov Identifier: NCT00489827
Recruitment Status : Completed
First Posted : June 21, 2007
Results First Posted : June 7, 2019
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
Region Örebro County
Blekingesjukhuset, Karlskrona
Information provided by (Responsible Party):
Rolf Svedjeholm, University Hospital, Linkoeping

Tracking Information
First Submitted Date  ICMJE June 19, 2007
First Posted Date  ICMJE June 21, 2007
Results First Submitted Date  ICMJE October 30, 2017
Results First Posted Date  ICMJE June 7, 2019
Last Update Posted Date September 16, 2020
Study Start Date  ICMJE October 2005
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 7, 2019)
Number of Participants With Perioperative Myocardial Infarction, Postoperative Heart Failure or Postoperative Mortality [ Time Frame: 30 days ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 20, 2007)
Composite of perioperative myocardial infarction, postoperative heart failure or postoperative mortality [ Time Frame: 30 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2020)
  • Degree of Perioperative Myocardial Injury [ Time Frame: perioperative ]
    p-CK-MB postoperative day 1, p-troponin-T postoperative day 3
  • Postoperative Hemodynamic State [ Time Frame: Until arrival to ICU ]
    Mixed venous oxygen saturation (SvO2) measured at weaning from cardiopulmonary bypass and on arrival to ICU
  • Postoperative Hemodynamic State in Patients With Severely Reduced Left Ventricular Ejection Fraction (LVEF<0.40) [ Time Frame: End of surgery ]
    Hemodynamic instability despite inotropes or need for IABP at the end of surgery in patients with severely reduced left ventricular ejection fraction (LVEF<0.40)
  • Postoperative Renal Function [ Time Frame: 30 days ]
    maximum p-creatinine value recorded postoperatively < 30 days
  • Number of Participants With Postoperative Stroke < 24 Hours [ Time Frame: 24 hours ]
    Incidence of Postoperative stroke < 24 hours of surgery verifed by CT-scan
  • ICU Stay [ Time Frame: ICU stay ]
    ICU duration of stay (hours)
  • Atrial Fibrillation [ Time Frame: Hospital stay ]
    Number of patients with atrial fibrillation recorded postoperatively
  • Severe Circulatory Failure in CCS Class IV Patients [ Time Frame: 30 days ]
    Severe circulatory failure according to prespecified criteria as judged by a blinded endpoints committee in CCS class IV patients
  • Long-term Survival [ Time Frame: 6 months - 10 years ]
    Late mortality - related to biochemical markers (troponin-T, mixed venous oxygen saturation, NT-proBNP) and intervention
Original Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2007)
  • Degree of perioperative myocardial injury: CK-MB postoperative day 1, troponin-T postoperative day 3 [ Time Frame: perioperative ]
  • Postoperative hemodynamic state: Mixed venous oxygen saturation + p-lactate, heart rate, systolic AP, diastolic AP, Pulmonary diastolic AP, CVP (weaning-arrival ICU) and NT-proBNP (24hrs, 3 days) [ Time Frame: Hours-3days ]
  • Postoperative cardiac output in patients with severely reduced left ventricular ejection fraction (LVEF<0.40) [ Time Frame: End of surgery ]
  • Postoperative renal function: p-cystatin C (postoperative day 3) and maximal p-creatinine recorded [ Time Frame: 30 days ]
  • Neurological safety issues: postoperative stroke (CT-scan) and p-100B (substudy n=70) [ Time Frame: 24 hours ]
  • ICU treatment: duration of stay and ventilator treatment, dialysis, circulatory support (pharmacological / mechanical) [ Time Frame: ICU stay ]
  • Atrial Fibrillation [ Time Frame: Hospital stay ]
  • Planned subgroup analyses: Patients requiring emergency surgery/intravenous nitrates, Patients with severely reduced LV-function, Diabetics, type of myocardial protection, OPCAB/ONCAB, combined CABG-valve procedures [ Time Frame: 30 days ]
  • Late mortality - related to biochemical markers (troponin-T, mixed venous oxygen saturation, NT-proBNP) and intervention [ Time Frame: 6 months - 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Glutamate for Metabolic Intervention in Coronary Surgery
Official Title  ICMJE Phase III Study of Intravenous Glutamate Infusion for Metabolic Protection of the Heart in Surgery for Unstable Coronary Artery Disease
Brief Summary The main purpose of this study is to determine whether intravenous glutamate infusion given in association with surgery for unstable coronary artery disease can protect the heart from myocardial injury, postoperative heart failure and death.
Detailed Description

Myocardial preservation in cardiac surgery has mainly focused on the period when the heart is arrested (cross-clamp time). Today the heart can be arrested for up to 2-3 hours without major consequences. However, in spite of comparatively short cross-clamp times approximately 10% of the patients undergoing coronary surgery sustain significant myocardial injury whereas perioperative myocardial infarction is rare in aortic valve surgery despite longer cross-clamp times. The reason for this is that preoperative ischemia, and to some extent postoperative ischemia, remain major risk factors for development of myocardial infarction in patients with ischemic heart disease. In light of this, we suggest that efforts to improve outcome and reduce permanent myocardial damage should focus on the preoperative and the postoperative phase of coronary surgery. Furthermore, efforts should be instituted to reduce reperfusion injury and minimize permanent myocardial damage in long-standing or severe myocardial ischemia.

Metabolic intervention with intravenous glutamate infusion, offers the prospect of addressing the issues above and extending myocardial protection into the pre- and postoperative phase. Glutamate is an important substrate for the intermediary metabolism of the heart, particularly in association with ischemia. The effects of glutamate are partly related to its role in the malate-aspartate shuttle, transporting reducing equivalents across the mitochondrial membrane, regulating the NAD/NADH balance in the cytosol of the cells, and thereby enhancing anaerobic glycolysis during ischemia. Furthermore, glutamate contributes to an alternative anaerobic pathway for regeneration of high-energy phosphates, by substrate level phosphorylation in the Krebs cycle. Glutamate also improves clearance of metabolic waste produced during ischemia such as lactate and NH3, by taking part in the reactions involving transamination of pyruvate to alanine and of glutamate to glutamine. During reperfusion glutamate contributes to the replenishment of Krebs cycle intermediates lost during ischemia, which is essential for recovery of oxidative metabolism.

Administration of glutamate to patients with stable angina pectoris has been found to increase tolerance to stress-induced ischemia. Ischemia before onset of cardiopulmonary bypass has been established as a major risk factor for postoperative myocardial infarction. Patients with unstable coronary artery disease may have critical ischemia at rest and are particularly vulnerable to the increased oxygen demands during the early stages of coronary surgery. In a pilot study on patients operated urgently for unstable angina we found metabolic signs compatible with improved tolerance to ischemia before surgery and improved recovery of oxidative metabolism during early reperfusion. These results warrant further studies to evaluate the potential clinical benefit of preoperative glutamate infusion extended into the early postoperative period.

Comparisons: Intravenous infusion of 0.125 M glutamic acid solution v saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.

Preliminary power analysis (80% power; p<0.05) suggests that 2214 patients will be required with regard to primary end-point assuming 30% reduction of events occurring in 12% of untreated patients.

Stage I of the study comprises 800 patients* and will lead to an interim analysis with report of secondary end-points** and recalculation of sample-size with regard to primary end-point. An adaptive design with regard to primary end-point and analysis performed by external statistician blinded to the investigators will be used to avoid increasing the risk for type I error.

*Patient number 800 is anticipated to be enrolled during the summer of 2009 and for practical reasons all patients enrolled until the end of August 2009 will comprise the interim analysis.

**Secondary end-points include analysis of markers for myocardial injury (CK-MB, troponin-T), markers for hemodynamic adequacy (mixed venous oxygen saturation), renal function (p-creatinine, p-Cystatin C), brain injury (S100B, clinical signs). As a substudy a blinded analysis of the value of NT-pro BNP (obtained immediately before surgery, 24 hours postoperatively and on the 3rd postoperative day) as marker of postoperative heart failure and outcome will be conducted. NT-pro BNP will also be related to treatment with glutamate or placebo. Similar evaluation will involve markers troponin-T, p-Cystatin C and mixed venous oxygen saturation. For further details see outcome measures.

Substudies will involve subgroup analyses of patients with regard to combined CABG + valve procedures, severely unstable patients requiring emergency surgery / intravenous nitrates, preoperative LV-dysfunction and patients with diabetes. For further details see outcome measures.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Coronary Artery Bypass
  • Myocardial Ischemia
  • Myocardial Infarction
  • Coronary Artery Disease
Intervention  ICMJE
  • Drug: Intravenous infusion of saline
    Intravenous infusion of isotonic saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
  • Other: Intravenous glutamate infusion
    Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
Study Arms  ICMJE
  • Active Comparator: Intravenous glutamate
    Intravenous infusion of 0.125 M glutamic acid solution at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
    Intervention: Other: Intravenous glutamate infusion
  • Placebo Comparator: Saline infusion
    Intravenous infusion of saline at a rate of 1.65 ml/hour and kg body weight beginning with institution of anesthesia and stopping 2 hours after unclamping of aorta in patients operated for unstable coronary artery disease.
    Intervention: Drug: Intravenous infusion of saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 7, 2019)
865
Original Estimated Enrollment  ICMJE
 (submitted: June 20, 2007)
800
Actual Study Completion Date  ICMJE October 2015
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • surgery for unstable coronary artery disease (unstable angina, non-STEMI)
  • accepted for surgery < 2 weeks after STEMI
  • coronary surgery for indications above performed with or without cardiopulmonary bypass
  • coronary surgery for indications above with or without simultaneous valve procedure

Exclusion Criteria:

  • informed consent not possible because of critical condition or other reason
  • preoperative use of inotropes or mechanical circulatory assist
  • preoperative dialysis
  • redo-procedure
  • unexpected intraoperative finding / event that increased the dignity of the procedure to overshadow the originally planned operation
  • body weight > 125 kg
  • food allergy known to have caused flush, rash or asthma
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 85 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00489827
Other Study ID Numbers  ICMJE 151:2003/70403
20030595 ( Registry Identifier: 151/2003/70403 Swedish Medical Product Agency) )
M76-05 ( Other Identifier: Regional Ethical Review Board in Linkoping )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rolf Svedjeholm, University Hospital, Linkoeping
Study Sponsor  ICMJE University Hospital, Linkoeping
Collaborators  ICMJE
  • Region Örebro County
  • Blekingesjukhuset, Karlskrona
Investigators  ICMJE
Study Director: Rolf Svedjeholm, MD PhD University Hospital, Linkoeping
PRS Account University Hospital, Linkoeping
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP